Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression. AAV-associated dendritic loss is accompanied by a decrease in the frequency and amplitude of miniature excitatory postsynaptic currents and an increase in the proportion of GluA2-lacking, calcium-permeable AMPA receptors. The AAV genome is rich in unmethylated CpG DNA, which is recognized by the innate immunoreceptor Toll-like receptor 9 (TLR9), and acutely blocking TLR9 preserves dendritic complexity and AMPA receptor subunit composition in AAV-injected mice. These results reveal unexpected impacts of an immune response to the AAV genome on neuronal structure and function and identify approaches to improve the safety and efficacy of AAV-mediated gene delivery in the nervous system.

中文翻译：

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对腺相关病毒基因组的先天免疫反应降低了皮质树突的复杂性并破坏了突触传递


重组腺相关病毒 (AAV) 可以将基因快速有效地传递到神经系统，广泛应用于神经科学研究，并且是 FDA 批准的神经元靶向基因疗法的基础。在这里，我们发现对 AAV 基因组的先天免疫反应减少了树突长度和复杂性，并破坏了小鼠体感皮层的突触传递。注射实验相关病毒滴度后 3 周，树突状损失很明显，不限于特定的衣壳血清型、转基因、启动子或生产设施，并且不能用对手术或转基因表达的反应来解释。 AAV 相关的树突损失伴随着微型兴奋性突触后电流的频率和幅度的降低以及缺乏 GluA2 的钙渗透性 AMPA 受体比例的增加。 AAV 基因组富含未甲基化的 CpG DNA，可被先天免疫受体 Toll 样受体 9 (TLR9​​) 识别，急性阻断 TLR9 可保留 AAV 注射小鼠的树突复杂性和 AMPA 受体亚基组成。这些结果揭示了 AAV 基因组的免疫反应对神经元结构和功能的意外影响，并确定了提高神经系统中 AAV 介导的基因传递的安全性和有效性的方法。